期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 38, 页码 12850-12864出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5351-13.2014
关键词
dendritic varicosities; HIV-1 Tat; intracellular sodium; mitochondrial hyperpolarization; opioid drug abuse; striatal medium spiny neurons
资金
- National Institute on Drug Abuse (NIDA) [R01 DA018633, R01 DA033200, K02 DA027374, K99 DA033878]
Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes to exaggerated inflammation and cognitive impairment seen in opioid abusers with HIV-1. To examine events triggering combined transactivator of transcription (Tat)- and morphine-induced synaptodendritic injury systematically, striatal neuron imaging studies were conducted in vitro. These studies demonstrated nearly identical pathologic increases in dendritic varicosities as seen in Tat transgenic mice in vivo. Tat caused significant focal increases in intracellular sodium ([Na+](i)) and calcium ([Ca2+](i)) in dendrites that were accompanied by the emergence of dendritic varicosities. These effects were largely, but not entirely, attenuated by the NMDA and AMPA receptor antagonists MK-801 and CNQX, respectively. Concurrent morphine treatment accelerated Tat-induced focal varicosities, which were accompanied by localized increases in [Ca2+](i) and exaggerated instability in mitochondrial inner membrane potential. Importantly, morphine's effects were prevented by the mu-opioid receptor antagonist CTAP and were not observed in neurons cultured from mu-opioid receptor knock-out mice. Combined Tat- and morphine-induced initial losses in ion homeostasis and increases in [Ca2+](i) were attenuated by the ryanodine receptor inhibitor ryanodine, as well as pyruvate. In summary, Tat induced increases in [Na+](i), mitochondrial instability, excessive Ca2+ influx through glutamatergic receptors, and swelling along dendrites. Morphine, acting via mu-opioid receptors, exacerbates these excitotoxic Tat effects at the same subcellular locations by mobilizing additional [Ca2+](i) and by further disrupting [Ca2+](i) homeostasis. We hypothesize that the spatiotemporal relationship of mu-opioid and aberrant AMPA/NMDA glutamate receptor signaling is critical in defining the location and degree to which opiates exacerbate the synaptodendritic injury commonly observed in neuroAIDS.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据